Cobimetinib Fumarate

Melanoma

In combination with vemurafenib for treatment of unresectable or metastatic melanoma with b-Raf serine-threonine kinase (BRAF) V600E or V600K mutation1 2 (designated an orphan drug by FDA for this use).3

FDA-approved in vitro diagnostic test (e.g., cobas 4800 BRAF V600 mutation test) required to confirm presence of BRAF V600E or V600K mutation prior to initiation of therapy.1 2

Not indicated for use in patients with wild-type BRAF melanoma.1

Limited data suggest greater efficacy (longer progression-free and overall survival, higher objective response rates) in patients with BRAF inhibitor-naive disease versus those with disease progression during prior BRAF inhibitor therapy.22 23

Contraindications

• Manufacturer states none known.1

Warnings/Precautions

Sensitivity Reactions

Photosensitivity reactions, sometimes severe, reported.1 2

Avoid exposure to sunlight during cobimetinib therapy.1 (See Advice to Patients.) If photosensitivity reactions occur, interrupt therapy, reduce dosage, or permanently discontinue drug.1 (See Dosage Modification under Dosage and Administration.)

Combination Therapy

When used in combination with vemurafenib, consider cautions, precautions, and contraindications of vemurafenib.1

Development of New Primary Malignancies

Cutaneous squamous cell carcinoma, keratoacanthoma, basal cell carcinoma, and new primary melanoma reported.1 2 Median time to detection of cutaneous squamous cell carcinoma, keratoacanthoma, or basal cell carcinoma was 4 months after initiating combination therapy with cobimetinib and vemurafenib in the coBRIM study in patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutation.1 New primary melanoma reported in 2 patients at 9 and 12 months after initiation of combination therapy with cobimetinib and vemurafenib.1

Noncutaneous malignancies reported in 0.8% of patients receiving cobimetinib in combination with vemurafenib compared with 1.2% of those receiving vemurafenib alone.1

Perform dermatologic evaluation at baseline and every 2 months during therapy; continue monitoring for 6 months following discontinuance of cobimetinib and vemurafenib.1 Initiate appropriate therapy and excise suspicious cutaneous lesions for pathologic evaluation.1

Monitor for new noncutaneous malignancies.1

Hemorrhage

Hemorrhage, including major hemorrhagic events (i.e., symptomatic bleeding in a critical area or organ), reported.1 Increased incidence of GI hemorrhage, reproductive system hemorrhage, or hematuria observed during combination therapy with cobimetinib and vemurafenib compared with vemurafenib alone.1 Cerebral hemorrhage reported in 2 patients receiving combination therapy compared with none of those receiving vemurafenib alone.1

If hemorrhagic events occur, interrupt therapy, reduce dosage, or permanently discontinue drug.1 (See Dosage Modification under Dosage and Administration.)

Cardiac Effects

Cardiomyopathy (i.e., symptomatic or asymptomatic decrease in LVEF), sometimes requiring temporary interruption, dosage modification, or permanent discontinuance of therapy, reported.1 2 Median time to first onset of left ventricular dysfunction was 4 months in the coBRIM study.1 Left ventricular dysfunction resolved (i.e., LVEF exceeded LLN or was within 10% of baseline) in most patients; median time to resolution was 3 months.1

Safety not established in patients with baseline LVEF below the LLN or <50%.1

Assess LVEF prior to and 1 month after initiation of therapy, then every 2–3 months during therapy.1 If left ventricular dysfunction occurs, interrupt therapy, reduce dosage, or permanently discontinue drug.1 (See Dosage Modification under Dosage and Administration.) Reassess LVEF approximately 2, 4, 10, and 16 weeks following reinitiation of the drug and then as clinically indicated.1

Dermatologic Effects

Severe dermatologic reactions, sometimes requiring hospitalization, reported.1 Median time to onset of grade 3 or 4 rash in patients receiving combination therapy with cobimetinib and vemurafenib was 11 days in the coBRIM study.1 Grade 3 or 4 rash resolved completely in most patients; median time to resolution was 21 days.1

If dermatologic reactions occur, interrupt therapy, reduce dosage, or permanently discontinue drug.1 (See Dosage Modification under Dosage and Administration.)

Ocular Effects

Ocular toxicities (e.g., serous retinopathy, retinal vein occlusion) reported.1 2 Serous retinopathy usually occurred 2 days to 9 months following initiation of therapy.1 Duration ranged from 1 day to 15 months.1

Perform ophthalmologic examinations regularly and as clinically indicated (i.e., if new or worsening visual disturbances occur) during therapy.1 If ocular toxicities occur, interrupt therapy, reduce dosage, or permanently discontinue drug.1 (See Dosage Modification under Dosage and Administration.)

Hepatic Toxicity

Liver function test abnormalities reported.1 2

Perform liver function tests prior to initiation of therapy and then monthly, or more frequently as clinically indicated.1 If liver function test abnormalities occur, interrupt therapy, reduce dosage, or permanently discontinue drug.1 (See Dosage Modification under Dosage and Administration.)

Musculoskeletal Effects

Rhabdomyolysis reported.22 Median time to first occurrence of grade 3 or 4 CK elevations was 16 days in patients receiving combination therapy with cobimetinib and vemurafenib in the coBRIM study; median time to complete resolution was 15 days.1

Evaluate serum CK and Scr concentrations at baseline, periodically during therapy, and as clinically indicated.1 If elevated CK concentrations occur, evaluate for manifestations of rhabdomyolysis and for other potential causes.1 If increased CK concentrations occur, interrupt therapy, reduce dosage, or permanently discontinue drug.1 (See Dosage Modification under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Embryotoxicity and teratogenicity demonstrated in animals.1

Pregnancy should be avoided during cobimetinib therapy and for ≥2 weeks after drug discontinuance.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1 (See Advice to Patients.)

Impairment of Fertility

May impair female and male fertility.1

Specific Populations

May cause fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Not known whether cobimetinib is distributed into milk.1 Discontinue nursing during therapy and for 2 weeks after drug discontinuance.1

Safety and efficacy not established.1

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1

Pharmacokinetic profile not established in patients with moderate to severe hepatic impairment.1 Exposure may be increased, since cobimetinib is principally metabolized by the liver.1

In a population pharmacokinetic analysis, systemic exposure not altered by mild hepatic impairment; dosage adjustment not necessary in such patients.1 (See Special Populations under Pharmacokinetics.)

Formal pharmacokinetic studies not conducted in patients with renal impairment.1

In a population pharmacokinetic analysis, systemic exposure not altered by mild or moderate renal impairment; dosage adjustment not necessary in such patients.1 21 (See Special Populations under Pharmacokinetics.)

Not studied in patients with severe renal impairment.1

Common Adverse Effects

Diarrhea,1 2 photosensitivity reaction,1 2 nausea,1 2 pyrexia,1 2 vomiting,1 2 acneiform rash,1 hypertension,1 vision impairment,1 stomatitis,1 chorioretinopathy,1 2 hemorrhage,1 retinal detachment,1 chills,1 arthralgia,2 elevated Scr concentrations,1 elevated CK concentrations,1 2 elevated AST or ALT concentrations,1 2 lymphopenia,1 elevated alkaline phosphatase concentrations,1 anemia,1 hypophosphatemia,1 elevated γ-glutamyltransferase (γ-glutamyltranspeptidase, GGT, GGTP) concentrations,1 hypoalbuminemia,1 hyponatremia,1 hyperkalemia,1 hypokalemia,1 hypocalcemia,1 thrombocytopenia.1

Principally metabolized by CYP3A and UGT2B7.1

Substrate of CYP3A.1 May inhibit CYP isoenzymes 3A and 2D6.1 At clinically relevant concentrations, does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, and 2C19 or induce CYP isoenzymes 1A2, 2B6, and 3A4.1

Substrate of P-glycoprotein (P-gp).1 Does not inhibit P-gp at clinically relevant concentrations.1

In vitro, neither a substrate nor inhibitor of breast cancer resistance protein (BCRP), organic cation transporter (OCT) 1, or organic anion transport protein (OATP) 1B1 and OATP1B3 at clinically relevant concentrations.1

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Possible increased systemic exposure of cobimetinib.1 Avoid concomitant use.1 (See Specific Drugs and Foods under Interactions.)

Moderate CYP3A inhibitors: Possible increased systemic exposure of cobimetinib.1 Simulations suggest that administration of cobimetinib 20 mg once daily with a moderate CYP3A inhibitor for <14 days results in steady-state concentrations similar to those achieved with cobimetinib 60 mg once daily alone.1 Avoid concomitant use.1 (See Specific Drugs and Foods under Interactions.) If concomitant short-term therapy (≤14 days) with a moderate CYP3A inhibitor cannot be avoided, reduce cobimetinib dosage from 60 mg once daily to 20 mg once daily; when the moderate CYP3A inhibitor is discontinued, resume prior cobimetinib dosage of 60 mg once daily.1 In patients receiving a reduced cobimetinib dosage (40 or 20 mg once daily), select alternative drug with no or mild CYP3A inhibitory activity.1

Moderate or potent CYP3A inducers: Possible decreased systemic exposure and reduced efficacy of cobimetinib.1 22 Simulations suggest that concomitant use of a potent or moderate CYP3A inducer may decrease cobimetinib exposure by 83 or 73%, respectively.1 Avoid concomitant use.1 (See Specific Drugs and Foods under Interactions.)

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2D6: Pharmacokinetic interaction not observed to date.1

Substrates of CYP3A: Pharmacokinetic interaction not observed to date.1

Drugs Affecting Efflux Transport Systems

Inhibitors of P-gp: Possible increased concentrations of cobimetinib.1

Specific Drugs and Foods

Absorption

Bioavailability

Absolute bioavailability is 46%.1

Following oral administration, peak plasma concentrations are attained in 2.4 hours.1

Mean systemic accumulation ratio is 2.4-fold when administered daily.1

Steady-state concentrations are achieved in approximately 9 days.1

Food

High-fat meal does not affect exposure.1

Special Populations

In patients with mild hepatic impairment, systemic exposure similar to that in patients with normal hepatic function.1 Pharmacokinetics not studied in patients with moderate or severe hepatic impairment.1

In patients with mild or moderate renal impairment, systemic exposure similar to that in patients with normal renal function.1 Pharmacokinetics not studied in patients with severe renal impairment.1

Age (19–88 years), gender, and ethnicity do not substantially affect pharmacokinetics.1 21

Distribution

Extent

Not known whether cobimetinib is distributed into milk.1 (See Lactation under Cautions.)

Plasma Protein Binding

95%.1

Elimination

Metabolism

Metabolized mainly by CYP3A and UGT2B7.1

Elimination Route

Eliminated mainly in feces (76%) and to a lesser extent in urine (17.8%), mainly as metabolites.1 22

Half-life

44 hours.1

• If a dose is missed or vomited, importance of taking the next dose at the regularly scheduled time; do not take an additional dose to replace the missed or vomited dose.1

• Risk of new primary cutaneous malignancies.1 Importance of contacting a clinician promptly if dermatologic changes (e.g., new wart, skin sore or reddish bump that bleeds or does not heal, mole that changes in size or color) occur.1

• Risk of hemorrhage.1 Importance of contacting a clinician promptly and seeking immediate medical attention if signs and/or symptoms of unusual bleeding (e.g., blood in stool or urine, unusual vaginal bleeding) occur.1

• Risk of cardiomyopathy.1 Importance of cardiac monitoring before and during cobimetinib therapy.1 Importance of contacting a clinician promptly if manifestations of left ventricular dysfunction (e.g., shortness of breath, persistent coughing or wheezing, fatigue, peripheral edema, tachycardia) occur.1

• Risk of serious adverse dermatologic effects.1 Importance of contacting a clinician promptly if a serious reaction (e.g., rash affecting a large area, blistering or peeling of skin) occurs.1

• Risk of serous retinopathy or retinal vein occlusion.1 Importance of contacting a clinician promptly if visual disturbances (i.e., blurred, distorted, partial, or halo vision) occur.1

• Risk of hepatotoxicity.1 Importance of liver function test monitoring before and during cobimetinib therapy.1 Importance of immediately reporting any possible manifestations of hepatotoxicity (e.g., jaundice, dark or tea-colored urine, nausea, vomiting, fatigue, loss of appetite).1

• Risk of rhabdomyolysis.1 Importance of monitoring CK concentrations before and during cobimetinib therapy.1 Importance of immediately reporting any possible manifestations of rhabdomyolysis (e.g., dark or red urine; muscle pain, spasms, or weakness).1

• Risk of photosensitivity reactions.1 Importance of using a broad-spectrum sunscreen and lip balm (SPF ≥30), wearing protective clothing, and avoiding exposure to sunlight during therapy.1 Importance of contacting a clinician if skin becomes red, painful, itchy, or warm; irritated; or thick, dry, or wrinkled; if bumps or small papules develop; or if a rash from sunlight exposure occurs.1

• Risk of fetal harm.1 Necessity of advising women of childbearing potential that they should use an effective method of contraception while receiving the drug and for ≥2 weeks after discontinuance of therapy.1 Importance of women informing clinicians if they are or plan to become pregnant.1 If pregnancy occurs, advise pregnant women of potential risk to the fetus.1

• Importance of advising women to avoid breast-feeding during and for 2 weeks after discontinuance of therapy.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John’s wort), as well as any concomitant illnesses.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)